San Antonio Breast Cancer Symposium 2014
SOFT Lands hard: Adjuvant Ovarian Suppression in Pre-menopausal Breast Cancer
Francis PA, Regan MM, Fleming GF et al.
Background: Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor–positive early breast cancer in pre-menopausal women, but its value when added to tamoxifen is uncertain.
Methods: 3066 pre-menopausal women, stratified according to prior receipt of chemotherapy or not, were randomized to receive either 5 years of (a) tamoxifen (b) tamoxifen plus ovarian suppression (OFS), or (c) exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus OFS would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal.
Results: After a median follow-up of 67 months (overall median age 43), the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen–OFS group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus OFS than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen–OFS group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane–OFS group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87).
CARE Faculty Canadian Perspective:
· In the SOFT trial with a median follow up of 67 months, for the primary study objective, the addition of ovarian suppression to tamoxifen did not provide a statistically significant benefit in the overall study population (5yDFS 84.7% Tam vs. 86.6% Tam+OFS, HR0.83, p=0.10).
· Of note, however, the SOFT trial enrolled essentially 2 cohorts of patients. The first cohort included 949 patients who were older (median age 46) with lower risk disease (smaller, lower grade disease and did not receive adjuvant chemotherapy). The 5 year DFS rate observed in this cohort of patients was >95%. No benefit was seen here with the addition of the OFS. The second cohort included 1084 women who remained biochemically pre-menopausal after adjuvant chemotherapy. This group of women tended to be younger (median age 40) and had higher risk disease characteristics. It is in this group the addition of OFS improved upon disease outcomes (5yDFS 78% Tamoxifen, 82.5% Tam+OFS HR 0.78 95%CI 0.60-1.02). As a secondary outcome objective even further improvement was seen with the use of exemestane plus OFS (5yDFS 85.7% HR 0.65 95%CI 0.49-0.87). The most striking benefit was seen in a smaller subset of women younger than 35 (who historically have a higher risk of relapse).
· The benefit of OFS needs to be weighed however against the increased rates of adverse events. Grade 3 or higher toxicity were reported in 31.3% in TAM+OFS vs, 23.7% Tam alone. Hot flushes, sweating, decreased libido, vaginal dryness, insomnia, depression, musculoskeletal symptoms, hypertension, and glucose intolerance being most frequently reported symptoms in Tam+OFS. Nonadherence rates to OFS also increased with each subsequent year of treatment (21.9% at year 4).
· The earlier reports of the combined analysis from TEXT and SOFT trials[ii] demonstrated that OFS+Exemestane were statistically significant when compared to OFS+Tamoxifen. The current SOFT analysis supports this finding with the greatest benefit seen in a higher risk, younger cohort of patients selected for chemotherapy and persistent premenopausal status.
· Apart from traditional prognostic risk factors, it would be ideal to be able to predict in advance who would benefit most (or least) from each adjuvant endocrine therapy strategy to help guide therapeutic choices. Until such time however, Oncologists are left with the daunting task of considering and explaining yet another evidence based adjuvant endocrine therapy option in pre-menopausal breast cancer patients beyond Tamoxifen for 5-10 years. For low risk patients, some clearly do well with Tamoxifen alone. For younger women (e.g. <35) with higher risk disease post chemotherapy, the addition of OFS x 5 years (+/- aromatase inhibitor) should be considered.
· The issue of how to best balance and manage the resultant potential adverse effects of treatment, while continuing to maintain treatment compliance will be no small task. The multidisciplinary team approach (with nursing and pharmacy colleagues) to care for these patients on an ongoing basis will be even more important than ever. Longer follow-up is still required (for both efficacy and toxicity evaluation) as the trial is currently underpowered and the overall survival analysis is still immature.
- CARE Breast Cancer Faculty
Francis PA, Regan MM, Fleming GF et al. Adjuvant Ovarian Suppression in Premenopausal Breast Cancer. N Engl J Med 2014 Dec 11. [Epub ahead of print]
Pagani, O, Regan, MM, Walley, BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. N Engl J Med 2014;371:107-118.